Aranoalkyl-z-tmenyl-cycloalkenyl



Patented July 24, 1951 AMINOALKYL-Z-THIENYL-CYCLOALKENYL ACETATE Frederick Leonard, Brooklyn, N. Y., assignor to Warner-Hudnut, Inc., New York, N. Y., a. corporation of Delaware No Drawing. Application October 1, 1949,

Serial No. 119,197

6 Claims. (01. zoo-294.3}

This invention relates to new compounds of pharmaceutical value, particularly as antispasmodics.

Two principal types of antispasmodic action are recognized. The first type, manifested by compounds such as atropine, is known as neurotropic action in that stimulation of the muscle is inhibited by action on the nerve cells. The other type, manifested by compounds such as papaverine, is known as musculotropic action in that stimulation of the muscle is inhibited by direct action on the muscle cells. While both papaverine and atropine have been employed clinically on a wide scale, there are many spastic conditions which are not relieved by either substance. Further, there is a considerable demand for products possessing both neurotropic and musculotropic activity.

In the search for more satisfactory and effective antispasmodics, aryl and cycloalkyl monoand disubstituted acetic acid esters of dialkylaminoalkanols have been developed. While these compounds have been found to possess both neurotropic and musculotropic activity and have attained a degree of clinical acceptance, their efficacy and toxicity is such that considerable improvement is desired.

It is an object of this invention to provide new compounds having the desirable combination of high musculotropic and neurotropic activity with low toxicity.

As a result of extensive investigation, I have found that a certain limited class of compounds, identified below, possess in an optimum degree the combination of both musculotropic and neurotropic antispasmodic action with low toxicity, so that they are definitely superior to the aryl or cycloalkyl acetic acid esters heretofore available. The compounds of my invention are characterized by the structural formula:

wy-E R" S CH 0 OAIkN in which R denotes a cyclohexenyl or cyclopentenyl radical; R and R which may be the same or different, denote alkyl radicals containing not over 4 carbon atoms, or together denote a polymethylene radical containing not over 5 carbon atoms, and which may be interrupted by an oxygen, sulfur or imino group; R denotes hydrogen, a short chain alkyl radical or halogen, which members may be the same or different; and All:

2 denotes an alkylene radical containing not over 6 carbon atoms and which may be straight chain or branched. These compounds have been found to possess excellent antispasmodic activity of both neurotropic and musculotropic nature, being more eflective than the aryl or cycloalkyl acetic acid esters above described. Furthermore, the toxicity of the compounds of this invention is considerably in which R, R and Alk are a above defined and Hal denotes halogen, with a compound of the formula (RWMU CHCOOH in which R and 1'1, are as above defined, or with an alkali salt thereof; this reaction may be carried out readily under reflux in a suitablesolvent such as isopropanol. My compounds may also be prepared by reacting under reflux and in a suitable solvent a compound of the formula NAlkOH 61 with an acyl halide of the thienyl acetic acids above illustrated. Another suitable method involves reacting a lower alkyl, e. g. methyl or ethyl, ester of the thienyl acetic acids above illustrated with an aikanol of the formula above given under conditions accomplishing ester interchange and volatilization of the lower alcohol, e. g. by heating tained by reacting diethyl-2-thienyl malonate with a cyclohexem'l or cyclopentenyl halide in a menses suitable solvent and at temperatures varying between and 78 C.

The free bases of my invention are water-insoluble solids. Water-soluble salts may be formed by treating the free bases with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, tartaric acid, citric acid or succinic acid, or with suitable organic halides, e. g. alkyl halides such as methyl chloride or methyl bromide, aralkyl halides such as benzyl cloride 0r benzyl bromide, or other organic halides such as thienylmethyl chloride.

The products of my invention have been found to be highly eifective antispasmodics. They may be administered orally in the form of tablets containin 50 to 75 mg. of the active ingredient, or parenterally in the form of aqueous solutions containing about of one of the water soluble salts herein described.

Extensive tests have established my compounds to have both neurotropic and musculotropic activity. In these tests, the results of which are set forth below, antispasmodic neurotropic activity was determined by suspending a strip of guinea pig intestine in a bath of oxygenated Locke's solution maintained at body temperature and inducing spasm by addition of an aqueous solution of acetyl choline in a concentration of one part per million; the quantity of compound being tested required to prevent development of spasm induced in this manner was then determined.

Musculotropic activity was determined in the same manner, except that barium chloride in a concentration of one part per five thousand was used to induce spasm. In addition, intravenous 'and subcutaneous toxicity in mice 01' the compounds tested was determined, expressed in terms of LD50 (lethal dose against 50% of test animals). The results of these tests are given below, together with comparative data obtained with the diphenyl acetic acid ester of diethylaminoethanol of the prior art. The compounds tested were as follows, each being in the form of its hydrochloride:

.It will be evident from the table that compounds I, II and III, compounds of this invention, are

more active antispasmodics in both their neurotropic and musculotropic activity than compound IV, and further that the compounds of my in'- vention are less toxic than compound IV.

Pharmacological tests have also indicated that the products of my invention are extremely etfective in protecting against bronchial asthma which may be induced by cholinergic drugs. Thus it has been established that subcutaneous doses of from 10 to 20 mg. per kg. of the compounds of this invention completely protected guinea pigs against bronchial asthma or other untoward effects following lethal doses of the cholinergic drug neostigmine. The compounds of my invention are also effective anti-histaminics.

The following examples are illustrative of my invention:

Examples 4.9 g. of sodium were dissolved in 150 cc. absolute ethanol, the solution cooled to 50 C. and 38.7 g. of ethyl-,2-thienyl malonate added; the mixture was then heated to reflux and cooled to 0 C. 39.7 g. 01 a toluene solution containremoved by vacuum distillation, 50 cc. of water were added and the organic layer separated; the aqueous layer was washed with toluene and the washings combined with the organic layer. The combined organic layers were washed with water, the toluene removed by vacuum distillation and the residual oil fractionated. The compound diethyl 2 thienyl A -cyclopenteny1 malonate, boiling at 175-185 C. at 5.5 mm., was recovered.

37.5 g. of the above compound, 27.4 g. potassium hydroxide, 27.4 cc. water and cc. 95% ethanol were then mixed and refluxed for 20 hours. At the end of this time the alcohol was removed by distillation and the residual oil dissolved in water and extracted with ether. The alkaline aqueous solution was then covered with ether and acidified by the addition of concentrated hydrochloric acid, during which time vigorous evolution of carbon dioxide occurred. The organic layer was then separated and the aqueous layer extracted with ether, washed and dried. Ether was then removed by evaporation and the residue distilled under vacuum, whereby 2-thienyl-A -cyclopentenyl acetic acid was obtained, boiling at 161-166 C. at 3 mm; Upon standing, the material crystallized to form a product melting at 60-65 C.

6.305 g. of the above product and 4.11 g. of' fi-diethylaminoethyl chloride were mixed with 80 cc. absolute isopropanol and refluxed for 48 hours. At the end of this time, the reaction mixture was cooled, filtered and solvent removed by evaporation. Ether was then added to the resultant oil, whereupon crystallization soon commenced. The crystals obtained were recovered by filtration, washed with ether and dried. The desired product, after recrystallization from a' mixture of isopropanol and ether, melted at 128- 130 C. and was identified as the hydrochloride of B diethylamino ethyl 2 thienyl A cyclopentenyl acetate.

By substituting for the n -cyclopentenyl chloride employed in the above example an equivalent amount of n -cyclohexenyl chloride, the compound 5 diethylaminoethyl 2 thienyl- A -cyclohexenyl acetate hydrochloride was obtained. Likewise. by substitutin for the p-diethylaminoethyl chloride in either of the above examples an equivalent amount of p-piperidinoethyl chloride, corresponding esters of p-piperidinoethanol may be obtained. In addition to the compounds above mentioned, the following additional compounds may be obtained by substituting suitable reactants in accordance with the foregoing disclosure in the procedure described in the above example: fl-diethylaminoethyl-3-methyl-2-thienyl-A -cyclopentenyl tate; p-diethylaminoethyl-i-chloro-2-thienyl-A=*- cyclohexenyl acetate; fi-dimethylaminoethyl-2- thienyl-A -cyclopentenyl acetate; B-di-isopropylaminoethyl-ii-thienyl-A cyclohexenyl acetate; 7 diethylamino B -methy1propyl 2 thienyl- A -cyclopentenyl acetate; fl-morpholinoetlwl-2- thienyl-M-cyclopentenyl acetate; p-thiomorph-' lin0methyl-2-thienyl-A cyclohexenyl acetate;

- p piperazl'noethyl 2 thienyl-A -cyclopentenyl ing the structural formula.

S CH0 0 olun/ in which R denotes a member selected from the 0 group consisting of cyclohexenyl and cyclopentenyl radicals; R" and R denote radicals selected from the group consisting of alkyl radicals containing not over 4 carbon atoms or together denote a radical selected from the group consisting of polymethylene radicals containing not over 5 carbon atoms and polymethylene radicals containing not over 4 carbon atoms interrupted by a member selected from the group consisting of oxygen, sulfur and imino substituents; R denotes a member selected from the group consisting of hydrogen, short chain alkyl radicals and halogens; and Alk denotes an alkylene radical containing not over 6 carbon atoms, and their salts.

2. The compounds of claim 1 in which R denotes hydrogen.

3. The compounds of claim 2 in which R and R denote alkyl radicals containing not over 4 carbon atoms.

4. A preparation having high neurotropic and musculotropic antispasmodic activity containing as its essential active ingredient the compound 5 diethylaminoethyl 2 thienyl A cyclopentenyl acetate hydrochloride.

5. A preparation having high neurotropic and musculotropic antispasmodic activity containing as its essential active ingredient the compound 3 diethylaminoethyl 2 thienyl A cyclohexenyl acetate hydrochloride.

6. A preparation having high neurotropic and musculotropic antispasmodic activity containing as its essential active ingredient the compound 5 piperidinoethyl 2 thienyl A cyclohexenyl acetate hydrochloride.

FREDERICK LEONARD.

REFERENCES CITED The following references are of record in the file of this patent:

Blicke: J. Am. Chem. Soc.. 66, pp. 1645-1648 (1 44).

Powers: Advancing Fronts in Chemistry, vol. 2, pp. 32-33 (1946).

Huttrer: Enzymologia, 12, 308 (1948). 

1. A PREPARATION HAVING NEUROTROPIC AND MUSCULOTROPIC ANTISPASMODIC ACTIVITY CONTAINING AS IT ESSENTIAL ACTIVE INGREDIENT A COMPOUND HAVING THE STRUCTURAL FORMULA 